tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Despite immense progress in immunotherapy, responses with available anti-PD-1 therapies remain low for patients with HPV-associated head and neck squamous cell cancer (HNSCCa). This clinical trial demonstrates that therapy with MEDI0457, a DNA immunotherapeutic agent targeting HPV 16/18 E6/E7 viral antigens, is safe and feasible. Aggarwal and colleagues demonstrate promising humoral immune activation, and elevated antigen-specific T-cell activity in a majority of the patients with HNSCCa. The findings suggest that HPV viral neoantigens can be targeted therapeutically as a complementary immune strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve patient outcomes.The current standard of care for first-line treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC) is the combination of chemotherapy with either an anti-EGFR or anti-VEGF monoclonal antibody. To identify a potential biomarker that enables a more personalized therapeutic approach for this patient population, Laurent-Puig and colleagues analyzed miR-31-3p expression in tumors from the RAS wild-type population enrolled in the FIRE-3 trial. Their analysis demonstrated the expression level of miR-31-3p is predictive of cetuximab efficacy for patient survival and response-related outcomes as compared with bevacizumab when combined with chemotherapy for first-line treatment of mCRC.Mismatch-repair-deficient (dMMR) tumors generally harbor abundant lymphocytic infiltrates, which are believed to contribute to their prognostic advantage and may underlie their enhanced responsiveness to immunotherapy. Yoon and colleagues examined CD3+ and CD8+ T-cell subtypes in stage III colon cancers from a large adjuvant trial. They found that the density of lymphocytic infiltrates in dMMR colon cancers exhibit greater intertumor heterogeneity than in MMR-proficient tumors. Lymphocyte densities also prognosticated within the dMMR group. This heterogeneity may be relevant for the efficacy of adjuvant immunotherapy, which is currently being studied in stage III colon cancers.T-cell acute lymphoblastic leukemia (T-ALL) is a fulminant blood cancer affecting children and adults. Despite improvements in patient survival on current therapy, frontline treatment will fail in up to 25% of children and 50% of adults, and prognosis for relapsed patients is poor. NOTCH1 is a main oncogene in T-ALL. Jin and colleagues demonstrate that the ubiquitin-specific protease 7 (USP7) interacts with the NOTCH1 complex and controls leukemia growth by stabilizing the levels of the complex and promoting oncogenic transcription. Ultimately, the group suggests a therapeutic modality in leukemia via targeting USP7.
Re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation Therapy. Eur Urol 2021;79:879–86 AR-V7 is Rare in Hormone-sensitive Prostate Cancer
Authors: Adam G. Sowalsky, Stephen R. Plymate, Michael C. Haffner, Johann S. de Bono, Adam Sharp
Journal: European Urology (2022)
Retraction: The Reversible Fourth-Generation EGFR Tyrosine Kinase Inhibitor OBX02-011 Overcomes C797S-Mediated Resistance in Lung Cancer
Authors: Yun Jung Choi, Da-Som Kim, Young Hoon Sung, Dong Ha Kim, Kyungtaek Im, Hyeonjeong Lee, Chae Won Lee, Jeongin Cho, Joongkee Min, Dong-Cheol Woo, Sung-Eun Kim, Sunho Lee, Yun Jeong Kong, Hyung Chul Ryu, Jae-Sun Kim, Rajesh Rengasamy, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho
Journal: Cancer Research (2022)

This article (1) has been retracted at the request of the authors. The accepted version of the article included the complete structure of OBX02-011 in keeping with AACR editorial policy and was published online on June 14, 2022. The authors subsequently decided not to disclose the complete structure (2) and requested to have the article retracted. The authors apologize to the scientific community and deeply regret any inconveniences or challenges resulting from the publication and subsequent retraction of this article.A copy of this retraction notice was sent to the last known email addresses for 20 of the 20 authors. A total of 13 authors (Yun Jung Choi, Da-Som Kim, Dong Ha Kim, Hyeonjeong Lee, Chae Won Lee, Sung-Eun Kim, Sunho Lee, Yun Jeong Kong, Rajesh Rengasamy, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho) agreed to the retraction; seven authors (Young Hoon Sung, Kyungtaek Im, Jeongin Cho, Joongkee Min, Dong-Cheol Woo, Hyung Chul Ryu, Jae-Sun Kim) did not respond.
Reply
Authors: Shikai Hu, Satdarshan P. Monga
Journal: Hepatology (2022)

We thank the authors of Hu et al. for their comments on our study.1 We understand the complexity of signaling pathways that can make the current study complicated for some to understand but are confident of its relevance and reproducibility. With regards to concern 1, relationship between hepatic mechanistic target of rapamycin complex 1 (mTORC1) and β‐catenin was shown in four ways. First, we identified compensatory activation of mTORC1 and its downstream effectors in β‐cateninΔHC mice after hepatectomy. Second, we showed demise of RaptorΔHC‐β‐cateninΔHC mice by 12 h and of RaptorΔHC mice by 48 h posthepatectomy. Third, RaptorΔHC mice without any challenge died at 40 days and showed early proliferative β‐catenin activation. RaptorΔHC‐β‐cateninΔHC mice showed demise by 30 days. Lastly, pharmacological inhibition of mechanistic target of rapamycin led to impaired liver regeneration (LR) and demise of β‐cateninΔHC by 14 days postsurgery. Collectively, our data demonstrate compensatory interplay between mTORC1 and β‐catenin signaling. For point 2, AAV8‐TBG–mediated gene deletion in our model should not disrupt pancreatic mTORC1 signaling.2 Decreased serum glucose level in Raptor knockouts has been reported due to compensatory AKT activation.3 Deleting Akt2 in the Raptor knockouts reversed changes in serum glucose and may be mediated by AKT‐driven glycogen synthase kinase 3 beta (GSK3β) phosphorylation and inactivation.3 We also observed increased AKT activation and GSK3β inactivation in RaptorΔHC mice. Thorough understanding of the intricacies of LR is important to appreciate the sequence of experimentation in our study. Also, because of the numbers of mice and time points, it is impossible to show every piece of data, but appropriate statistics were always included. Analysis of known mitogenic and developmental pathways during LR in β‐cateninΔHC mice was inconsequential. We identified insulin‐mTORC1 signaling as one possible mechanism driving LR in these mice. We did not address the role of Wnt‐dependent stabilization of proteins signaling, which may be agnostically contributing to cell division in LR.4 It is unlikely that Wnt/mTORC1 pathway signaling is playing a role in LR in β‐cateninΔHC mice because we did not see any difference in LDL related protein 6 phosphorylation.5 Eventually, we agree that, as a responsible researcher, it is pertinent to be cautious in interpreting every scientific study because there often are multiple explanations underlying an observation.
ADAR1 Prevents Autoinflammatory Processes in the Heart Mediated by IRF7
Authors: Claudia Garcia-Gonzalez, Christoph Dieterich, Giovanni Maroli, Marion Wiesnet, Astrid Wietelmann, Xiang Li, Xuejun Yuan, Johannes Graumann, Konstantinos Stellos, Thomas Kubin, Andre Schneider, Thomas Braun
Journal: Circulation Research (2022)

Background: ADAR1 (adenosine deaminase acting on RNA-1)-mediated adenosine to inosine (A-to-I) RNA editing plays an essential role for distinguishing endogenous from exogenous RNAs, preventing autoinflammatory ADAR1 also regulates cellular processes by recoding specific mRNAs, thereby altering protein functions, but may also act in an editing-independent manner. The specific role of ADAR1 in cardiomyocytes and its mode of action in the heart is not fully understood. To determine the role of ADAR1 in the heart, we used different mutant mouse strains, which allows to distinguish immunogenic, editing-dependent, and editing-independent functions of ADAR1. Methods: Different Adar1 -mutant mouse strains were employed for gene deletion or specific inactivation of ADAR1 enzymatic activity in cardiomyocytes, either alone or in combination with Ifih1 (interferon induced with helicase C domain 1) or Irf7 (interferon regulatory factor 7) gene inactivation. Mutant mice were investigated by immunofluorescence, Western blot, RNAseq, proteomics, and functional MRI analysis. Results: Inactivation of Adar1 in cardiomyocytes resulted in late-onset autoinflammatory myocarditis progressing into dilated cardiomyopathy and heart failure at 6 months of age. Adar1 depletion activated interferon signaling genes but not NFκB (nuclear factor kappa B) signaling or apoptosis and reduced cardiac hypertrophy during pressure overload via induction of Irf7 . Additional inactivation of the cytosolic RNA sensor MDA5 (melanoma differentiation-associated gene 5; encoded by the Ifih1 gene) in Adar1 mutant mice prevented activation of interferon signaling gene and delayed heart failure but did not prevent lethality after 8.5 months. In contrast, compound mutants only expressing catalytically inactive ADAR1 in an Ifih1 -mutant background were completely normal. Inactivation of Irf7 attenuated the phenotype of Adar1 -deficient cardiomyocytes to a similar extent as Ifih1 depletion, identifying IRF7 as the main mediator of autoinflammatory responses caused by the absence of ADAR1 in cardiomyocytes. Conclusions: Enzymatically active ADAR1 prevents IRF7-mediated autoinflammatory reactions in the heart triggered by endogenous nonedited RNAs. In addition to RNA editing, ADAR1 also serves editing-independent roles in the heart required for long-term cardiac function and survival.
Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia
Authors: Brennan P. Bergeron, Jonathan D. Diedrich, Yang Zhang, Kelly R. Barnett, Qian Dong, Daniel C. Ferguson, Robert J. Autry, Wenjian Yang, Baranda S. Hansen, Colton Smith, Kristine R. Crews, Yiping Fan, Ching-Hon Pui, Shondra M. Pruett-Miller, Mary V. Relling, Jun J. Yang, Chunliang Li, William E. Evans, Daniel Savic
Journal: Leukemia (2022)

Abstract Glucocorticoids (GCs) are a mainstay of contemporary, multidrug chemotherapy in the treatment of childhood acute lymphoblastic leukemia (ALL), and resistance to GCs remains a major clinical concern. Resistance to GCs is predictive of ALL relapse and poor clinical outcome, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis -regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cell lines using functional genomics and high-throughput reporter assays and identified thousands of GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and a depletion of AP-1 bound cis -regulatory elements implicated in cell proliferation and anti-apoptotic processes. By integrating our GC response maps with genetic and epigenetic datasets in primary ALL cells from patients, we further uncovered cis -regulatory disruptions at GC-responsive genes that impact GC resistance in childhood ALL. Overall, these data indicate that GCs initiate pervasive effects on the leukemia epigenome, and that alterations to the GC gene regulatory network contribute to GC resistance.
The Polypill at 20 — What Have We Learned?
Authors: Thomas J. Wang
Journal: New England Journal of Medicine (2022)

Next year marks the 20th anniversary of the first appearance of the polypill in the medical literature. Wald and Law coined the term to denote a fixed-dose combination of medications for preventing cardiovascular disease.1 They suggested that administering a polypill to all adults 55 years of age or older would reduce cardiovascular events by more than 80%. This concept generated immediate debate and a fair amount of resistance in the cardiovascular community.2 The Wald and Law proposal involved unconventional ways of thinking about who should be treated (nearly everyone) and how to deliver the therapy (with a daily combination pill). . . .
Polypill Strategy in Secondary Cardiovascular Prevention
Authors: Jose M. Castellano, Stuart J. Pocock, Deepak L. Bhatt, Antonio J. Quesada, Ruth Owen, Antonio Fernandez-Ortiz, Pedro L. Sanchez, Francisco Marin Ortuño, Jose M. Vazquez Rodriguez, Alexandra Domingo-Fernández, Iñigo Lozano, Maria C. Roncaglioni, Marta Baviera, Andreana Foresta, Luisa Ojeda-Fernandez, Furio Colivicchi, Stefania A. Di Fusco, Wolfram Doehner, Antje Meyer, François Schiele, Fiona Ecarnot, Aleš Linhart, Jean-Claude Lubanda, Gyorgy Barczi, Bela Merkely, Piotr Ponikowski, Marta Kasprzak, Juan M. Fernandez Alvira, Vicente Andres, Hector Bueno, Timothy Collier, Frans Van de Werf, Pablo Perel, Moises Rodriguez-Manero, Angeles Alonso Garcia, Marco Proietti, Mikkel M. Schoos, Tabassome Simon, Jose Fernandez Ferro, Nicolas Lopez, Ettore Beghi, Yannick Bejot, David Vivas, Alberto Cordero, Borja Ibañez, Valentin Fuster
Journal: New England Journal of Medicine (2022)

A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction.In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke.A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups.Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).
Updated Clinical Classification of Pulmonary Hypertension
Authors: Gérald Simonneau, Ivan M. Robbins, Maurice Beghetti, Richard N. Channick, Marion Delcroix, Christopher P. Denton, C. Gregory Elliott, Sean P. Gaine, Mark T. Gladwin, Zhi-Cheng Jing, Michael J. Krowka, David Langleben, Norifumi Nakanishi, Rogério Souza
Journal: Journal of the American College of Cardiology (2009)
Antisense Suppression of the Chloride Intracellular Channel Family Induces Apoptosis, Enhances Tumor Necrosis Factor α-Induced Apoptosis, and Inhibits Tumor Growth
Authors: Kwang S. Suh, Michihiro Mutoh, Michael Gerdes, John M. Crutchley, Tomoko Mutoh, Lindsay E. Edwards, Rebecca A. Dumont, Pooja Sodha, Christina Cheng, Adam Glick,, Stuart H. Yuspa
Journal: Cancer Research (2005)

Abstract mtCLIC/CLIC4 is a p53 and tumor necrosis factor α (TNFα) regulated intracellular chloride channel protein that localizes to cytoplasm and organelles and induces apoptosis when overexpressed in several cell types of mouse and human origin. CLIC4 is elevated during TNFα-induced apoptosis in human osteosarcoma cell lines. In contrast, inhibition of NFκB results in an increase in TNFα-mediated apoptosis with a decrease in CLIC4 protein levels. Cell lines expressing an inducible CLIC4-antisense construct that also reduces the expression of several other chloride intracellular channel (CLIC) family proteins were established in the human osteosarcoma lines SaOS and U2OS cells and a malignant derivative of the mouse squamous papilloma line SP1. Reduction of CLIC family proteins by antisense expression caused apoptosis in these cells. Moreover, CLIC4-antisense induction increased TNFα-mediated apoptosis in both the SaOS and U2OS derivative cell lines without altering TNFα-induced NFκB activity. Reducing CLIC proteins in tumor grafts of SP1 cells expressing a tetracycline-regulated CLIC4-antisense substantially inhibited tumor growth and induced tumor apoptosis. Administration of TNFα i.p. modestly enhanced the antitumor effect of CLIC reduction in vivo. These results suggest that CLIC proteins could serve as drug targets for cancer therapy, and reduction of CLIC proteins could enhance the activity of other anticancer drugs.
Annual Mortality Related to Pulmonary Embolism in the U.S. Before and During the COVID-19 Pandemic
Authors: Ioannis T. Farmakis, Luca Valerio, Behnood Bikdeli, Jean M. Connors, George Giannakoulas, Samuel Z. Goldhaber, Lukas Hobohm, Beverley J. Hunt, Karsten Keller, Alex C. Spyropoulos, Stefano Barco
Journal: Journal of the American College of Cardiology (2022)
Infection control at mass religious gatherings
Authors: Eskild Petersen, Danny Asogun, Francine Ntoumi, Alimuddin Zumla
Journal: BMJ (2022)

Infectious diseases that can cause epidemics are an ongoing risk to global health security. 1Mass gatherings such as religious, sporting, and festival events attract millions of people from across the world and create optimal conditions for importation, acquisition, transmission, and onward spread of infectious diseases, 2 3 including monkeypox.
Prothrombin induced by vitamin K Absence-II versus alpha-fetoprotein in detection of both resectable hepatocellular carcinoma and early recurrence after curative liver resection: A retrospective cohort study
Authors: Ming-Da Wang, Li-Yang Sun, Guo-Jun Qian, Chao Li, Li-Hui Gu, Lan-Qing Yao, Yong-Kang Diao, Timothy M. Pawlik, Wan Yee Lau, Dong-Sheng Huang, Feng Shen, Tian Yang
Journal: International Journal of Surgery (2022)
Group- vs Home-Based Exercise Training in Healthy Older Men and Women
Authors: Abby C. King
Journal: JAMA (1991)

<h3>Objective.</h3> —To determine the effectiveness of group- vs home-based exercise training of higher and lower intensities among healthy, sedentary older adults. <h3>Design.</h3> —Year-long randomized, controlled trial comparing (1) higher-intensity group-based exercise training; (2) higher-intensity home-based exercise training; (3) lower-intensity home-based exercise training; or (4) assessment-only control. <h3>Setting.</h3> —General community located in northern California. <h3>Participants.</h3> —One hundred sixty women and 197 men 50 to 65 years of age who were sedentary and free of cardiovascular disease. One out of nine persons contacted through a community random-digit-dial telephone survey and citywide promotion were randomized. <h3>Interventions.</h3> —For higher-intensity exercise training, three 40-minute endurance training sessions per week were prescribed at 73% to 88% of peak treadmill heart rate. For lower-intensity exercise training, five 30-minute endurance training sessions per week were prescribed at 60% to 73% of peak treadmill heart rate. <h3>Main Outcome Measures.</h3> —Treadmill exercise test performance, exercise participation rates, and heart disease risk factors. <h3>Results.</h3> —Compared with controls, subjects in all three exercise training conditions showed significant improvements in treadmill exercise test performance at 6 and 12 months (<i>P</i>&lt;.03). Lower-intensity exercise training achieved changes comparable with those of higher-intensity exercise training. Twelve-month exercise adherence rates were better for the two home-based exercise training conditions relative to the group-based exercise training condition (<i>P</i>&lt;.0005). There were no significant training-induced changes in lipid levels, weight, or blood pressure. <h3>Conclusions.</h3> —We conclude that (1) this community-based exercise training program improved fitness but not heart disease risk factors among sedentary, healthy older adults; (2) home-based exercise was as effective as group exercise in producing these changes; (3) lower-intensity exercise training was as effective as higher-intensity exercise training in the home setting; and (4) the exercise programs were relatively safe. (JAMA. 1991;266:1535-1542)
Reconstructing auto tissue engineering lamellar cornea with aspartic acid modified acellular porcine corneal stroma and preconditioned limbal stem cell for corneal regeneration
Authors: Yingwei Wang, Liling Xu, Jupeng Zhao, Jinchao Liang, Zhongxia Zhang, Qi Li, Jianhua Zhang, Pengxia Wan, Zheng Wu
Journal: Biomaterials (2022)